tbuckley/cabot-search huggingface dataset:
Abstract 1274: Extrinsic photoaging vs intrinsic aging in dermal fibroblasts: Its impact on the microenvironment and melanoma progression
Authors: Vania Wang, Yash Chhabra, Laura Hueser, Sneha Pramod, Alexis Carey, Ashani Weeraratna
Journal: Cancer Research (2023)

Abstract Melanoma is the deadliest form of skin cancer, with its incidence rising disproportionally to other cancers. Chronological aging is a major risk factor in all types of cancer as it has been shown to drive changes in noncancerous cells (stromal and immune) of the tumor microenvironment (TME) to promote tumor initiation and progression. Ultraviolet radiation (UVR) exposure, which is a major risk factor for melanoma, also can cause a physical premature aging phenotype, known as photoaging. Photoaging of the skin often occurs in tandem with chronological aging, and contributes to the physical features of aging through similar alterations in normal skin structure (eg. collagen degradation). However, the molecular mechanisms of how photoaging compares to chronological aging in changing the TME and on tumor progression is still lacking.Preliminary data have indicated that photoaging of young dermal fibroblasts induce some similar signature changes to that of intrinsically aged. We have shown in-vitro that UVA exposure in young fibroblasts cause upregulation in MMP-1, a matrix remodeling protein, and downregulation in β-catenin, the cell adhesion transcription regulator. These same changes were also shown in chronologically aged fibroblasts. In addition, both photoaging and chronological aging decreases ECM structural integrity, with increased collagen fragmentation and a reduction in the renewal of cross-linking proteins. To investigate how photoaging contributes to the pro-tumorigenic microenvironment of the aged dermis, we are using biochemical and phenotypic assays to study how chronic UVA exposure induces an intrinsically aged-like fibroblast behavior and secretome. We also hypothesize that photoaged fibroblasts reprogram the TME to become more permissible for the growth of tumor cells, and will test changes in invasion and metastasis or melanoma both in-vitro and in-vivo.Studying the impact of photoaging on aging in the skin microenvironment will help identify therapeutic targets and have direct clinical applications for cancer patients. Citation Format: Vania Wang, Yash Chhabra, Laura Hueser, Sneha Pramod, Alexis Carey, Ashani Weeraratna. Extrinsic photoaging vs intrinsic aging in dermal fibroblasts: Its impact on the microenvironment and melanoma progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1274.
Abstract 4204: Incidence of early-onset and average-onset colon cancer among Medicaid beneficiaries with and without HIV: a cohort study
Authors: Corinne Joshu, Keri Calkins, Jacqueline E. Rudolph, Xiaoqiang Xu, Eryka Wentz, Maneet Kaur, Filip Pirsl, Sally B. Coburn, Richard D. Moore, Bryan Lau
Journal: Cancer Research (2023)

Abstract Background: Colorectal cancer has increased among people living with HIV (PLWH). Studies have reported either no difference or lower risk of colorectal cancer incidence among PLWH as compared to the general population. We evaluated the incidence of colon cancer, both average-onset (diagnosed at 50 or older) and early-onset (diagnosed at less than 50), among a diverse population of people with and without HIV who have comparable sociodemographic factors and access to care. Methods: We obtained Medicaid Analytic eXtract (MAX) data from 2001-2015 for 14 states. We included 42,244,679 unique individuals with at least 7 months of continuous eligibility. HIV and colon cancer diagnoses were identified from inpatient and other non-drug claims. We used Cox proportional hazards regression models to assess the incidence of colon cancer, controlling for age, sex, race/ethnicity, calendar year of enrollment, state of enrollment, and number of comorbidities. Analyses were also adjusted for or stratified by age, sex, and race/ethnicity. Findings: We identified 191 colon cancer cases among 523,969 person-years among PLWH and 15,098 colon cancer cases among 63,579,078 person-years among beneficiaries without HIV. Colon cancer incidence increased with age among beneficiaries with and without HIV. Overall, HIV was modestly, inversely associated with colon cancer incidence (HR:0.84, 95%CI: 0.73, 0.98). PLWH 18-39 years old had increased hazard of colon cancer as compared to those without HIV (HR:1.67, 95%CI: 1.06, 2.65); this association was attenuated after adjustment for co-morbidities. HRs were null when early-onset colon cancer was assessed among all beneficiaries less than 50 years. PLWH had lower hazard of average-onset colon cancer compared to those without HIV (HR:0.81, 95%CI: 0.68, 0.96); this association was statistically significant among male, but not female, beneficiaries. Interpretation: Compared to beneficiaries without HIV, PLWH had a lower risk of average-onset colon cancer. PLWH had higher incidence of early-onset colon cancer, but this difference was attenuated after adjustment for comorbid conditions. Citation Format: Corinne Joshu, Keri Calkins, Jacqueline E. Rudolph, Xiaoqiang Xu, Eryka Wentz, Maneet Kaur, Filip Pirsl, Sally B. Coburn, Richard D. Moore, Bryan Lau. Incidence of early-onset and average-onset colon cancer among Medicaid beneficiaries with and without HIV: a cohort study. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4204.
Abstract 1704: Interferon inducible ADAR1 is essential for the survival of oral squamous cell carcinoma
Authors: Pei San Yee, Annie Wai Yeeng Chai, Shi Mun Yee, Shi Yin Ooi, Yee Hua Tan, Mathew Garnett, Siew Kit Ng, Sok Ching Cheong
Journal: Cancer Research (2023)

Abstract Treating oral squamous cell carcinoma (OSCC) remains challenging due to limited knowledge of the critical genes that could affect cell survival in OSCC. We have previously utilized genome-wide CRISPR-Cas9 knockout functional screens to explore the genetic vulnerabilities of OSCC and identified Adenosine deaminase acting on RNA (ADAR1) as one of the top fitness genes. ADAR1 is an interferon-stimulated gene (ISG) that catalyses adenosine-to-inosine (A-to-I) editing of double-stranded RNA (dsRNA), which suppresses dsRNA sensing mechanism from triggering cell death. ADAR1 gene encodes for two isoforms, the constitutively expressed P110 and the interferon-inducible P150. Given that deleting ADAR1 severely impacts OSCC viability, we aimed to elucidate key molecular mechanisms underlying this gene dependency which may provide opportunities for developing better treatment strategies. Here, we validated ADAR1 dependency via competitive co-culture assay using single-guide RNA (sgRNA) knockout in selected OSCC cell lines. We also confirmed that sgRNA-mediated ADAR1 knockout resulted in prominent cell lethality through increased apoptosis and inhibition of colony formation. Cell lethality is evident in ADAR1 KO cells in conjunction with the phosphorylation of a dsRNA sensor, protein kinase R (PKR) which regulates cell death mechanism. In ADAR1-less dependent cells, IFN-β treatment increased the expression of ISGs including ADAR1, and sensitized the cells to ADAR1 KO-induced cell death. Overexpression of ADAR1-P150 but not ADAR1-P110 rescued cell lethality in ADAR1-depleted cells, suggesting that ADAR1-P150 is required for OSCC survival. We also demonstrate that the deaminase function of ADAR1 is important in conferring survival to a subset of OSCC lines. In addition to PKR, the melanoma differentiation-associated protein 5 (MDA5) dsRNA sensor is also important in mediating ADAR1 KO-induced cell lethality OSCC and co-deleting both PKR and MDA5 enabled the partial rescue of cell death compared to when each gene was knocked out individually. Collectively, our results uncover the essentiality of IFN-inducible ADAR1-P150 for OSCC survival, and reveal that the activation of PKR and MDA5 dsRNA sensing pathways underlie the cell lethality caused by ADAR1 deletion. Citation Format: Pei San Yee, Annie Wai Yeeng Chai, Shi Mun Yee, Shi Yin Ooi, Yee Hua Tan, Mathew Garnett, Siew Kit Ng, Sok Ching Cheong. Interferon inducible ADAR1 is essential for the survival of oral squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1704.
Abstract 2456: Transcriptional signatures of stem cell phenotypes in normal and clonal hematopoiesis
Authors: Ruslan Soldatov, Giulia Schiroli, Peter Kharchenko, David Scadden
Journal: Cancer Research (2023)

Abstract Clonal hematopoiesis (CH) is an age-related clonal expansion of hematopoietic stem cells (HSCs). Factors that shape the progression of CH are only beginning to be characterized. HSCs are a heterogeneous population of cells with distinct clonal outputs over time, which are hypothesized to be largely scripted in epigenetic and transcriptional cell state. Molecular properties of HSC states that mediate clonal behaviors of two major driver mutations in CH - DNMT3A and TET2 - represent potential therapeutical targets. Recent studies have identified the landscape of human CH mutant cells compared to non-mutated ones. However, the notion of a specific molecular target identified in CH cells associated with selective advantage or predisposition for subsequent transformation requires a formal validation by longitudinal studies. To uncover molecular underpinnings of CH-driven clonal phenotypes in human HSCs in vivo, we combined clonal analysis using heritable expressed DNA barcodes with single-cell transcriptomics using transplant in immunodeficient mice. We developed a statistical approach to associate transcriptional differences of HSCs with the clone phenotypes, such as size and HSC density, across more than a hundred of detected clones. It revealed robust transcriptional signatures underlying clone size and HSC density, which are largely complementary to transcriptional programs activated in TET2 and DNMT3A mutant HSCs. Of note, the clone size and density of HSCs in the clone tend to be uncoupled and associated with distinct transcriptional processes. Citation Format: Ruslan Soldatov, Giulia Schiroli, Peter Kharchenko, David Scadden. Transcriptional signatures of stem cell phenotypes in normal and clonal hematopoiesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2456.
Abstract 4066: Lipid nanoparticle library towards development next generation genomic medicines
Authors: Anitha Thomas, Nikita Jain, Sedigheh Nazaripour, Rehan Higgins, Zhengyu Chen, Suraj Abraham, Leanna Yee, Srinivas Abbina, Gayatri Mehar Namala, Helena Son, Sams Sadat, Sijo Chemmannur, Malathi Anantha, Ruchi Sharma, Kobe Tickner, Eve Boyer, Shannon Tsai, Seetalakshmi Thambatti, Vinay Mayya, Emily Soon, Jay Paquette
Journal: Cancer Research (2023)

Abstract Ionizable amino lipids are a major constituent of the lipid nanoparticles for delivering nucleic acid therapeutics (e.g., DLin-MC3-DMA in ONPATTRO®, ALC-0315 in Comirnaty®, SM-102 in Spikevax®). Scarcity of lipids that are suitable for cell therapy, vaccination, and gene therapies continue to be a problem in advancing many potential diagnostic/therapeutic/vaccine candidates to the clinic. Herein, we describe the development of novel ionizable lipids to be used as functional excipients for designing vehicles for nucleic acid therapeutics/vaccines in vivo or ex vivo use in cell therapy applications. We first studied the transfection efficiency (TE) of LNP-based mRNA formulations of these ionizable lipid candidates in primary human T cells and established a workflow for engineering of primary immune T cells. We then adapted this workflow towards bioengineering of CAR constructs to T cells towards non-viral CAR T therapy. Lipids were also tested in rodents for vaccine applications using self-amplifying RNA (saRNA) encoding various antigens. We have then evaluated various ionizable lipid candidates and their biodistribution along with the mRNA/DNA translation exploration using various LNP compositions. Further, using ionizable lipids from the library, we have shown gene editing of various targets in rodents. We believe that these studies will pave the path to the advancement in nucleic acid based therapeutics and vaccines, or cell &amp; gene therapy agents for early diagnosis and detection of cancer, and for targeted genomic medicines towards cancer treatment and diagnosis. Citation Format: Anitha Thomas, Nikita Jain, Sedigheh Nazaripour, Rehan Higgins, Zhengyu Chen, Suraj Abraham, Leanna Yee, Srinivas Abbina, Gayatri Mehar Namala, Helena Son, Sams Sadat, Sijo Chemmannur, Malathi Anantha, Ruchi Sharma, Kobe Tickner, Eve Boyer, Shannon Tsai, Seetalakshmi Thambatti, Vinay Mayya, Emily Soon, Jay Paquette. Lipid nanoparticle library towards development next generation genomic medicines. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4066.
Abstract 387: Enolase-1 as a candidate theranostics target for neuroendocrine prostate cancer
Authors: Krystal Rubi Santiago Torres, Alfonso Duran
Journal: Cancer Research (2023)

Abstract Prostate cancer (PCa) is the second most common cancer in American men, with men of African ancestry (AA) having twice the mortality of men of European ancestry (EA). Although taxane-based chemotherapy is the last line of defense in men with advanced PCa, it ultimately fails due to chemoresistance. The protein-specific membrane antigen (PSMA) has been an effective target for the imaging and therapy of advanced PCa. Specifically, PSMA radioligand therapy (PSMA-RLT) is a theranostics (therapy + diagnostics) option for men with advanced PCa. However, about 30% of men with advanced PCa have limited response to PSMA-RLT due to the presence of neuroendocrine-differentiated PCa (NEPC), which lacks PSMA expression. A promising alternative to PSMA targeting is the glycolytic enzyme enolase (ENO), which localizes to the cell surface in advanced tumors. There are three enolases with similar functions, with ENO-1 and ENO-2 implicated in PCa. Here, we demonstrate, using immunoblotting, confocal microscopy, and cell fractionation studies with specific monoclonal antibodies, that chemosensitive NEPC cells express both ENO-1 and ENO-2; however, docetaxel (DTX)-resistant PC3-DR and DU145-DR cells only express ENO-1 with clear loss of ENO-2. Loss of ENO-2 in chemoresistant PCa cells generates a metabolic vulnerability due to loss of ENO redundancy. We also initiated the testing of small molecule inhibitors (SMIs) targeting ENO-1 in chemoresistant and chemosensitive NEPC cells, showing that these inhibitors have cytotoxic activity against these cells, with IC50 values in the low micromolar range. These results support the hypothesis that ENO-1 is expressed in the surface of NEPC cell lines and can be targeted with SMIs that could be modified as potential theranostics agents. Our long-term goal is to identify an alternative treatment for patients with NEPC by establishing ENO-1 as a novel cell surface theranostics target. Citation Format: Krystal Rubi Santiago Torres, Alfonso Duran. Enolase-1 as a candidate theranostics target for neuroendocrine prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 387.
Abstract 4238: Specific oral microbiome is closely associated with oral potentially malignant disorders and oral squamous cell carcinoma
Authors: Mitomu Kioi, Hiroshi Isono, Shintaro Nakajima
Journal: Cancer Research (2023)

Abstract Background: Bacterial and virus infection may cause pre-malignant and malignant disorder such as hepatocellular carcinoma and cervical cancer. Recent studies reported that oral bacterium is associated with gastric and colon cancer. However, it is not clear yet if the oral microbiome affects the development of pre-malignant disorder in oral cavity and oral cancer. Thus, this study aims to identify the periodontal pathogen candidates involved in the onset and progression of oral squamous cell carcinoma (OSCC). Materials and Methods: Saliva was collected from 112 patients without oral mucosal diseases (OMDs) as control, 36 patients with oral potentially malignant disorders (OPMDs), and 104 patients with OSCC, and DNA was extracted in each sample. Periodontal examinations were performed on all patients. Endpoint-PCR was performed on seven species of oral pathogens using the extracted DNA. 16S ribosomal RNA (rRNA) was utilized for analysis of oral microbiome with 20 samples in each group. 4-nitroqquinoline-1-oxide (4-NQO)-induced tongue tumor model in mice was analyzed with or without endotoxin of one of the oral bacteria, Porphyromonas gingivalis (P. gingivalis). Results: From the statistical analysis of the clinical parameters, periodontal disease tended to worsen in the OMPD and OSCC groups compared to the control group. The number of oral bacteria was significantly higher in the OSCC group than those in other groups. From PCR results, the detection rates of P. gingivalis, Aggregatibacter actinomycetemcomitans, and Treponema denticola were significantly higher in the OSCC group than those in the control group. From 16S rRNA analysis, the relative abundance of Prevotella buccae and intermedia was significantly higher in OSCC groups than in the control group. Furthermore, the relative abundance of P. gingivalis was higher in the OSCC group compared to other groups, regardless of age and the number of teeth. In mouse model, mice treated with P. gingivalis-derived endotoxin developed oral leukoplakia at earlier time points and tumors significantly higher lesions compared to control group. Conclusion: These results suggest that specific periodontal pathogens are present in the oral cavity of OPMDs and OSCC patients and those changes in the bacterial flora due to their presence may contribute to the onset and progression of OMDs. Citation Format: Mitomu Kioi, Hiroshi Isono, Shintaro Nakajima. Specific oral microbiome is closely associated with oral potentially malignant disorders and oral squamous cell carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4238.
Abstract 6705: Molecular detection of circulating cancer cells with cancer stem cell or mesenchymal characteristics in esophageal squamous cell carcinoma
Authors: Zhen Tan, Josephine Mun-Yee Ko, Valen Zhuoyou Yu, Hoi Yan Ng, Simon Law, Maria Li Lung
Journal: Cancer Research (2023)

Abstract Esophageal squamous cell carcinoma (ESCC) is a clinically challenging disease that requires a multidisciplinary approach. Unfortunately, the scarcity of ESCC genomic data hinders the understanding of ESCC biology, disease progression and rational therapy design. Circulating tumor cells (CTCs), which are shed from the primary and metastatic tumors and then circulate within the peripheral vasculature, reflect the existing tumor heterogeneity. Here, we utilized the non-biased size-based CTC enrichment strategy in combination with the real-time RT-PCR to molecularly characterize the CTCs with cancer stem cell (CSC) or mesenchymal properties in ESCC. Comprehensive data from ESCC cell lines, mouse ESCC xenograft models and clinical ESCC peripheral blood samples emphasize the importance of TWIST1 (Twist Family BHLH Transcription Factor 1) in ESCC progression. Gain-of-function and loss-of-function analyses demonstrate that TWIST1 promotes cell migration, invasion and colony formation in ESCC cells. Moreover, positive TWIST1 expression is responsible for the chemoresistance of ESCC cells to Cisplatin and is correlated with poor overall survival in ESCC patients. In addition, we show that TWIST1 promotes malignant potential, including tumor growth, invasion and chemoresistance via the TWIST1-TGFBI-ZEB1 signaling pathway in ESCC. Meanwhile, the TWIST1-TGFBI-ZEB1 signaling pathway confers immunosuppressive conditions to the tumor microenvironment, which in turn contributes to EMT to promote tumor progression. Collectively, these findings indicate that TWIST1 has a novel role in ESCC carcinogenesis by regulating tumorigenicity and cancer stem cell properties that may be useful as a prognostic monitoring biomarker and a promising therapeutic target in clinical ESCC treatment. Citation Format: Zhen Tan, Josephine Mun-Yee Ko, Valen Zhuoyou Yu, Hoi Yan Ng, Simon Law, Maria Li Lung. Molecular detection of circulating cancer cells with cancer stem cell or mesenchymal characteristics in esophageal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6705.